Patent GB-846045-A (GB)
Title: 11,12 epoxy steroids
IPC: C07J71/00
Filed: 1958-03-12
Abstract: The invention comprises steroid compounds of the general formula: <FORM:0846045/IV(b)/1> wherein R1 represents hydrogen or a hydroxy group or an acyloxy group such as an alkanoyloxy group containing 2 to 4 carbon atoms, or an o -carboxyalkanoyloxy group containing 3 or 4 carbon atoms or an alkali metal salt thereof, X represents an a -hydroxymethylene group or an a -acyloxymethylene group such as an a -alkanoyloxymethylene group containing 3 to 5 carbon atoms, or an a -(o -carboxyalkanoyl)-oxymethylene group containing 4 to 5 carbons or an alkali metal salt thereof, or when R1 is other than hydrogen, a keto group, and "\sm" represents an a -or preferably a b -bond.  The compounds may be prepared by several routes all of which have the same initial step, i.e. the oxidation of the 11b , 12b -epoxy-3, 20b -diol-preferably with chromic acid in acid solution such as in acetic acid, or chromic oxide in basic solution such as an excess of pyridine, to form 11b , 12b -epoxy-3, 20-diones.  The 3a -ol compounds of the above general formula may be prepared by selective reduction of the 3-keto analogues, i.e. the 11,12-epoxy-pregnane-3,20-diones which may or may not be substituted in the 21-position with a hydroxy or acyloxy group, with sodium borohydride or other bimetallic hydrides such as potassium borohydride or lithium aluminium hydride.  The 21-acyloxy compounds may also be prepared by preparing an 11b , 12b -epoxypregnane-3a -ol-20-one by the above reduction method, treating this compound with a halogen acid-preferably hydrogen bromide, to form, for example, a 12-bromo-11-ol, brominating this compound to form, for example, a 12,21-dibromopregnane-3a , 11-diol-20-one, reacting this compound with an alkali metal salt of the desired carboxylic acid to form the 21-ester group, and reacting this compound with an alkali metal salt such as sodium bicarbonate or potassium carbonate to form the 11b , 12b -epoxy ring (the last two steps may be carried out simultaneously).  The 21-esters may be further esterified at the 3-position to introduce the same or different ester group. The 3,21-diacylates may also be prepared by hydrolysing the 21-esters prepared as above and then diacylating the resulting 3,21-dihydroxy compound.  The 11a ,12a -epoxypregnane-3a -ol-20-ones may be prepared by reacting the D 1 1-pregnene analogue with a peracid such as perbenzoic, peracetic or perphthalic acid to form 11a ,12a -epoxypregnane-3,20-dione which may then be reduced and acylated by the above methods used for 11b ,12b -epoxypregnane-3,20-dione.  The acylate groups may be derived from oleic, palmitic, isobutyric, stearic, benzoic, phthalic, nicotinic, b -naphthoic, glycolic, glutaric cyclopentylpropionic, phenylacetic, maleic, acetic, propionic and succinic acids.  The 3-keto-21-oxygenated compounds of the above general formula are preferably prepared by oxidation of the 3a -ols.  In the examples 11b ,12b -epoxypregnane-3,20-dione, 11b ,12b -epoxypregnane-3a  -ol-20-one 11b ,12b -epoxypregnane-3a , 21-diol-20-one and various esters thereof, 11b 12b -epoxypregnane-3a -ol-20-one and the 3-acetate thereof, 11a 12a -epoxypregnane-3,20-dione and 11a ,12a -epoxypregnane-3a -ol-20-one and the isocaproate thereof, and the intermediate compounds 12-bromopregnane-3a ,11-diol-20-one and 12,21-dibromopregnane-3a ,11-diol-20-one are prepared. Pregnane-3,11,20-trione-21-ol-21-acetate is prepared by treating 11b ,12b -epoxypregnane-3,20-dione-21-ol with hydrogen bromide to form the corresponding 12-bromo-11-hydroxy compound, and oxidising and debrominating this compound with chromic oxide in pyridine and zinc in acetic acid respectively.